Introduction

Much of the research in this laboratory involves the study of interactions between the nervous and immune systems. Using knockout mice and over-expression in vivo with viral vectors, we are exploring the role of the neuropoietic cytokine leukemia inhibitor factor (LIF) in regulating neural stem cell proliferation and fate in the adult brain. In the context of neuroimmune interactions during fetal brain development, we are investigating a mouse model of mental illness based on the known risk factor of maternal influenza infection. Huntington’s disease (HD) is another focus, where we are investigating potential therapies using intracellular expression of antibodies (intrabodies) and also manipulating NFkB activity.

Cytokines are diffusible, intercellular messengers that were originally studied in the immune system. Our group contributed to the discovery of a family that we have termed the neuropoietic cytokines, because of their action in both the nervous and hematopoietic/immune systems. We demonstrated that one of these cytokines, LIF, can coordinate the neuronal, glial and immune reactions to injury. Using both delivery of LIF in vivo and examination of the consequences of knocking out the LIF gene in mice, we find that this cytokine has a powerful regulatory effect on the inflammatory cascade. Moreover, LIF can regulate neurogenesis and gliogenesis. LIF is a critical regulator of astrocyte and microglial activation following stroke, seizure or trauma, and this cytokine also regulates inflammatory cell infiltration, neuronal and oligodendrocyte death, gene expression, as well as adult neural stem cell renewal. These results highlight LIF as an important therapeutic target. We are currently examining the role of LIF in a chemical model of multiple sclerosis, where exogenous LIF can increase oligodendrocyte number and stimulate remyelination.

Cytokine involvement in a model for mental illness is also being investigated. This mouse model is based on findings that maternal infection can increase the likelihood of schizophrenia or autism in the offspring. We are using behavioral, neuropathological, molecular and brain imaging methods to investigate the effects of activating the maternal immune system on fetal brain development and how this leads to altered behavior in young and adult offspring. Recent results indicate that the cytokine IL-6 is key in mediating the effects of maternal immune activation on fetal brain development.

We are utilizing intracellular antibody expression to block the toxicity of mutant huntingtin (Htt), the protein that causes HD. We have produced single chain intrabodies that bind to various domains of Htt, and these can either exacerbate or alleviate Htt toxicity in cultured cells, acute brain slices, and in Drosophila HD models. Current work is evaluating the efficacy of viral delivery of intrabodies in several mouse models of HD. Promising results have recently been obtained in one of the mouse models. We have also implicated the NFkB signaling pathway in the pathogenesis of HD, and identified several steps in this signaling cascade as potential therapeutic targets.

Support: The work described in the following research reports has been supported by:

Anne P. and Benjamin F. Biaggini Chair in Biological Sciences

Autism Speaks Foundation

California Institute of Regenerative Medicine

Caltech Brain Imaging Center Discovery Grant

Foundation Blanceflor Boncopagni-Lu Dovisi

Hereditary Disease Foundation

John Douglas French Alzheimer’s Foundation

McGrath Foundation

McKnight Neuroscience of Brain Disorders Award

National Institute of Aging

National Institute of Mental Health

National Institute of Neurological Disease and Stroke

National Research Service Award, National Institutes of Health

Simons Foundation

Weston Havens Foundation

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This page last updated August, 2008 by C. Patterson